# Functional characterization of schizophrenia rare variants using genetically engineered human iPSCs

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $703,284

## Abstract

PROJECT SUMMARY
Schizophrenia (Scz) is a common and debilitating neurodevelopmental disorder. However, the genetic
architecture of Scz is highly complex, impeding research progress. Recently, the Scz Exome Meta-Analysis
(SCHEMA) Consortium has identified genes with ultra-rare coding variants that each confer substantial risk for
Scz. We hypothesize that the presence of these rare variants in human induced pluripotent stem cells (hiPSCs)
will lead to neuronal phenotypes relevant to Scz. The PI, Dr. Pan Li, has extensive experience with gene editing
and iPSCs, including development of an improved method for seamless introduction and removal of mutations
into hiPSCs. She has previously focused on neurodegenerative disorders, but with this application proposes to
change to study of Scz. This transition is facilitated by the location of her lab in the Division of Neurobiology,
which has a long track record of research into major mental illnesses and of highly collaborative research using
iPSCs (eg the HD iPSC Consortium). In Specific Aim 1, isogenic hiPSC lines with protein truncating variants
associated with Scz will be genetically engineered by CRISPR-assisted homologous recombination to generate
panels of iPSC lines, with each isogenic line bearing a different N-terminal protein truncating point mutation.
Knockdown and overexpression rescue experiments will determine whether there is loss of protein expression
and thus loss of gene function. In Specific Aim 2, the effect of mutations on gene and protein expression will
be studied using RNA seq and quantitative proteomics. In Specific Aim 3, the effects of mutations on synaptic
and electrophysiological phenotypes will be delineated. We hypothesize that understanding the cellular
phenotypes and altered signaling pathways evoked by the SCHEMA mutations will clarify the cellular
pathogenesis of subtypes of schizophrenia, and provide potential therapeutic targets.

## Key facts

- **NIH application ID:** 10757749
- **Project number:** 5R01MH129277-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Pan Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $703,284
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757749

## Citation

> US National Institutes of Health, RePORTER application 10757749, Functional characterization of schizophrenia rare variants using genetically engineered human iPSCs (5R01MH129277-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10757749. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*